[51-year-old patient with reversible infarct-like ECG changes].
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Coronary Vasospasm↗
Biomedical subjects
G König
Publications and source records attributed to G König.
Bcl-xl-specific antibody labels activated microglia associated with Alzheimer's disease and other pathological states.
This report describes the production of a monoclonal antibody raised against Bcl-xl, and includes an initial study of bcl-xl expression in neuropathology including Alzheimer's disease (AD). Bcl-xl is a potent apoptotic inhibitor and is known to be the predominant Bcl-x isoform in brain. To examine the expression of bcl-xl in aged brain and neurodegenerative disease, we raised a Bcl-xl-specific monoclonal antibody. In aged human brain, the highest bcl-xl expression was observed in cerebellum. By immunohistochemistry, significant bcl-xl expression was detected in reactive microglia of patients with AD and other neurological diseases such as progressive supranuclear palsy. Bcl-xl-positive microglia frequently colocalized with beta-amyloid plaques in AD and with activated astrocytes in non-AD and AD brains, suggesting a general role for Bcl-xl in regions of pathology. High levels of Bcl-xl protein might render microglia more resistant to cytotoxic environments such as areas of neurodegeneration and astrogliosis.
Aging↗
Finger exostosis caused by drumming? Comment on the clinical image report by Buttgereit and Burmester.
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Exostoses↗
[Marine organisms--producers of pharmacologically active secondary metabolites].
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Marine Biology↗
Blastocystis hominis in animals: incidence of four serogroups.
In toto, 520 faecal samples from mammals, birds, reptiles, amphibians, fish, and snails were investigated (see Table 1). 91 strains of Blastocystis hominis could be isolated by culture. However, only 48 of them were suitable for axenisation. 96 percent of samples belonged to four serogroups detected in humans but two strains, one from a pig and another from a duck, could not be classified, suggesting the existence of one or two further serogroups. While humans showed mainly serogroups I and II, pigs harboured serogroups III and IV. Four serogroups were isolated from monkeys. The question whether the genus Blastocystis consists of one or more species is discussed.
Amphibians↗
Development and characterization of a monoclonal antibody 369.2B specific for the carboxyl-terminus of the beta A4 peptide.
The beta-amyloid deposits in Alzheimer's diseased (AD) brain are made up mainly of beta A4 peptides which show both N- and C-terminal heterogeneity. The predominant C-terminal species, identified by peptide sequencing of purified beta-amyloid, end either at position 40 or 42 of the beta A4 peptide. The distribution of these two beta A4 species in postmortem tissue as well as their generation in vitro could not be addressed previously due to the lack of specific antibodies that could differentiate them. This report describes the generation of a highly specific monoclonal antibody, MAb 369.2B which was raised against a synthetic peptide consisting of the C-terminus of the 1-42 beta A4 species. MAb 369.2B does not recognize the shorter beta A4 species 1-40 in solution or in solid phase. Furthermore, both beta A4 1-40 and 1-43 were unable to absorb out the antibody when used immunocytochemically. The regional distribution of MAb 369.2B immunoreactivity in AD and non-AD brain samples were compared to MAb 286.8A, an antibody raised against the N-terminal region of beta A4. Overall, the staining patterns were very similar. In AD cases with extreme vascular involvement, the N-terminal (MAb 286.8A) antibody was more likely to label the vascular basement membrane of affected vessels, and to label them more uniformly. In addition, preliminary quantitative analyses revealed that the C-terminal antibody labeled fewer, larger plaques than the N-terminal antibody. Qualitative analyses revealed that these smaller plaques were typically subregions of the larger plaques. The data corroborate the biochemical findings of N-terminal raggedness in beta A4 plaques. Further studies are required to explain this differential pattern of deposition.
Aged↗
Immunohistochemical detection of factor XIIIa and factor XIIIs in synovial membranes of patients with rheumatoid arthritis or osteoarthritis.
In spite of differences in etiology, RA and OA lead to astonishingly similar synovitic alterations. Fibroblastic transformation of the synovial membrane and an increase in monocytes constitute a rare but highly characteristic feature of RA. Monocytes synthesize factor (F) XIII, implying that FXIII (a and s) in synovial tissue might help to differentiate between RA and OA. Biopsies were obtained at open surgery from 98 unselected patients with the clinical diagnosis of RA (n = 54) or OA (n = 44). In a three-stage (ABC) immunoperoxidase technique, polyclonal antisera against factor XIIIa and factor XIIIs were investigated. Compared to OA sections. RA synovium showed more FXIIIa-positive cells-monocytes, fibrocytes, fibroblasts and synovial lining cells. In the subsynovial layer, band-like structure of FXIIIa-stained cells was observed in 27.8% of the RA patients, but in only one OA specimen. Higher proportions of FXIIIa-positive monocytes, macrophages, histiocytes and fibroblasts, as well as positive Langhans giant cells and vascular wall regions (except endothelial cells), were observed in RA. OA specimens revealed more intense FXIIIa labeling of these cells with a lower percentage of stained cells. Overall, labeling with FXIIIs antibody resulted in less intense staining. In conclusion, distinction between synovitis caused by RA and synovitis due to OA is possible, as the former show higher numbers of FXIIIa-positive cells, including monocytes, fibroblasts, fibrocytes and synovial lining cells. Further more, RA tissue is stained less intensely than OA tissue. There is evidence for continuous excretion of FXIII in the synovial membrane by the above-mentioned cell systems.
Adolescent↗
Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung.
Fibrosing alveolitis (FA) is a frequent and often fatal complication of systemic sclerosis (SSC). Alveolar inflammation has been recognized as a primary event in the pulmonary manifestation of SSC. To evaluate the significance of the alveolitis in SSC, we performed bronchoalveolar lavage (BAL) and correlated the generated data with changes in lung function over time. Seventy nine SSC patients with pulmonary involvement were followed for 56.8 +/- 3.1 wk (mean +/- SEM) with a repeat lung function test at the end of the follow-up period. During follow-up, 38 patients were treated with a systemic immunosuppressive regimen. For evaluation, patients were assigned to two groups according to whether their BAL cell differential was normal (inactive BAL) or abnormal (active BAL: i.e., polymorphonuclear leukocytes > 5% and/or lymphocytes > 15%). Active BAL was associated with more severe lung function impairment than was inactive BAL, and patients with active BAL deteriorated during follow-up if untreated. In contrast, treated patients with active BAL stabilized or improved. In summary, active alveolitis as characterized by BAL is associated with progressive pulmonary disease in SSC patients, and a significant positive effect of immunosuppressive therapy on the course of pulmonary disease was observed in patients with active BAL.
Bronchoalveolar Lavage↗
[40-year-old patient without previous illness with acute shock symptoms and disseminated intravascular coagulation].
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Adult↗
The effect of the JE (MCP-1) gene, which encodes monocyte chemoattractant protein-1, on the growth of HeLa cells and derived somatic-cell hybrids in nude mice.
To investigate the effect of tumor-associated macrophages on the in vivo growth properties of cervical carcinoma cells, tumorigenic human papilloma virus (HPV) 18-positive HeLa cells were transfected with an expression vector harboring the cDNA for the macrophage chemoattractant protein-1 JE (MCP-1). Although the endogenous gene is present and not structurally rearranged, its expression seems to be negatively affected by a still unknown mechanism. Inoculation of JE (MCP-1)-negative HeLa cells into nude mice led to rapidly growing tumors, where macrophage infiltration into the inner tumor mass was not detectable immunohistochemically. The activity that attracted mononuclear cells under both in vitro and in vivo condition was reconstituted in HeLa cells after transfection with the JE (MCP-1) expression vector. Heterotransplantation of those cells into immunocompromised animals resulted in significant growth retardation that was accompanied by a strong infiltration of macrophages. On the other hand, in vivo selection of nonmalignant hybrids made between wild-type HeLa cells and normal human fibroblasts in nude mice resulted in tumorigenic segregants 4 mo after inoculation into the animals. Monitoring JE (MCP-1) expression directly within those nodules, we found that transcription was either absent or only weakly detectable. Recultivation of JE (MCP-1)-positive tissue grafts under in vitro conditions revealed that the gene was only marginally inducible by tumor necrosis factor-alpha, a cytokine that normally induces a very strong activation of transcription in nontumorigenic cells. These findings suggest that functional JE (MCP-1) expression and in turn activated macrophages may play a pivotal role in controlling the proliferation rate of HPV-positive cells in vivo.
Animals↗
Technetium-99m mercaptoacetyltriglycine clearance: reference values for infants and children.
Six hundred and thirty-nine clearance studies performed in children aged 7 days to 19 years utilizing technetium-99m mercaptoacetyltriglycine (MAG 3) were retrospectively analysed. Standardized conditions for the investigation included: parenteral hydration (60 ml/hxm2 body surface) in addition to normal oral fluid intake, weight-related dose of 99mTc-MAG 3 (1 MBq/kg body weight, minimum 15 MBq) and calculation of clearance according to Bubeck et al. Of the 513 children, 169 included in this analysis could be classified as "normal" with regard to their renal function. Normal kidney function was judged by the following criteria: normal GFR for age, normal tubular function (absence of proteinuria and glucosuria), normal renal parenchyma (on ultrasonography, MAG 3 scan and intravenous pyelography), absence of significant obstruction and gross reflux (>grade I), no single kidney and no difference in split renal function >20%. Results showed increasing MAG 3 clearance values for infants during the first months of life, reaching the normal range for older children and adults between 7 and 12 months.
Adolescent↗
Processing of the pre-beta-amyloid protein by cathepsin D is enhanced by a familial Alzheimer's disease mutation.
A major pre-beta-amyloid protein695 (APP695) processing activity from Alzheimer's disease brain extracts was identified and found to be indistinguishable from the activity of cathepsin D.APP695 processing activity cleaved APP695 into a series of fragments that reacted on immunoblots to a monoclonal antibody (C286.8a) against beta-amyloid-(1-7)-peptide and cleaved N-dansyl-APP-(591-601)-amide at the Glu-Val and Met-Asp bonds. Fragments of 5.5 kDa and 10-12 kDa were formed from the cleavage of APP695 by cathepsin D at the Glu593-Val594 bond, and had the same N-terminus as a minor form of beta-amyloid released by cells. The Lys595-->Asn and Met596-->Leu substitutions found in a pedigree of familial Alzheimer's disease, increased the cathepsin D-catalyzed rate of accumulation of 5.5 kDa and 10-12 kDa C286.8a-reactive fragments 5-10fold. This substitution also increased the rate of N-dansyl-APP-(591-601)-amide cleavage at the Xaa-Asp bond by up to 41-fold. These observations suggest a role of cathepsin D in beta-amyloid formation under certain circumstances.
Alzheimer Disease↗
Short-term and long-term effects of serial bronchoalveolar lavages in a nonhuman primate model.
Bronchoalveolar lavage (BAL) has gained widespread use as a tool for investigating human lung diseases. In certain cases, it can be useful to obtain BAL material in a serial manner. There is convincing evidence from experimental and clinical studies that BAL can cause influx of neutrophils into the bronchoalveolar space. However, conflicting data have been reported on whether this side effect of BAL also affects previously nonlavaged lung areas. In addition, there is little information available on whether multiple repetitive BAL procedures cause damage to lung tissue. To reexamine the short-term effects of serial BAL procedures, the left lung of 10 cynomolgus monkeys was lavaged with five 20-ml aliquots of saline four times at 24-h intervals (Group A). 72 h after the initial BAL, the right lung was lavaged as a control. The percentage of neutrophils increased significantly (p < 0.05), with the greatest effect seen at 48 h (30.7 +/- 5.8 versus 0.8 +/- 0.3%, mean +/- SEM). No significant changes were observed in the control BAL of the right lung at 72 h. A multidisciplinary approach was used to assess the long-term effects of multiple BAL procedures. BAL was performed 14 times over 26 mo at 2-mo intervals (Group B, n = 5). The right lung was lavaged as a control 25 mo after the initial BAL. In addition to standard cellular BAL parameters, the concentrations of fibronectin, procollagen III amino-terminal peptide-related antigen, total phospholipids, and lactate dehydrogenase activity were measured.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Regulation and expression of the Alzheimer's beta/A4 amyloid protein precursor in health, disease, and Down's syndrome.
A four- to fivefold overexpression of the gene for the Alzheimer beta/A4 amyloid precursor protein (APP) in individuals with Down's Syndrome (DS) appears to be responsible for the fifty year earlier onset of Alzheimer's disease (AD) pathology in DS compared to the normal population. It is therefore likely that a deregulated overexpression of the APP gene is a risk factor for the beta/A4 amyloid formation. To test this hypothesis and to get a better understanding of how APP expression is regulated, we studied the 5' control region of the human APP gene, alternative splicing of the 19 APP exons, and APP biogenesis, metabolism and function. The analysis of the APP promoter revealed its similarity with those of housekeeping genes by the presence of a GC-rich region around the transcription start site and the lack of a TATA box. Gene transfer experiments showed this GC-rich region to contain overlapping binding sites for different transcription factors whose binding is mutually excluded. An imbalance between these factors may cause APP overexpression and predispose to AD pathology. Another putative risk factor for AD is regulation of splicing of exon 7 in APP mRNA's which changes in brain during aging. This is relevant for APP processing since exon 7 codes for a Kunitz protease inhibitory domain. Investigation of further splicing adjacent to the beta/A4 exons 16 and 17 which might also interfere with APP processing led to the identification of the leukocyte-derived (L-APP) splice forms which lack exon 15. In brain this splicing occurs in activated astrocytes and microglia. The localization of APP at synaptic sites in brain suggests that APP regulation and expression are critical determinants of a potential and early impairment of central synapses. This may be the case during pathological evolution of AD and DS when beta/A4 derived from synaptic APP is converted to beta/A4 amyloid by radical generation.
Aging↗
Expression of L-APP mRNA in brain cells.
Several reports addressed the issue of how the alternative splicing of exon 7 and 8 in the APP pre-mRNA is regulated in different tissues. Of special interest here was the potential involvement of exon 7 containing APP splice isoforms, since this exon codes for a serine protease inhibitor and is therefore of putative relevance for amyloidogenic catabolism of the precursor protein. The recent identification of a third alternative splice site in close proximity to the beta A4-amyloid portion in the APP gene which may also increase APP amyloidogenicity, allowed us to investigate its regulation in cells of the central nervous system. With our assay, we were able to resolve six different APP isoforms of the eight potential isoforms which can be generated from the three alternatively spliced exons 7, 8, and 15. We demonstrate here that, in addition to rat brain microglia cells, astrocyte-enriched cultures also skip the novel alternative 3'-splice site in front of exon 15, generating L-APP mRNA. Neurons are the only cells in the central nervous system which seem to use the 3'-splice site of intron 14 nearly 100%. Interestingly, this very 3'-splice site is the only one present in the APP gene that completely matches the consensus sequence for the branchpoint sequence proposed for introns. We would therefore suggest that neurons lack a specific splicing factor which inhibits the use of the rather strong 3'-splice site in front of exon 15. It remains to be shown whether this is also the case for neurons in Alzheimer's disease.
Alternative Splicing↗
Early and rapid de novo synthesis of Alzheimer beta A4-amyloid precursor protein (APP) in activated microglia.
Upon acute activation, microglia, the immuneffector cells of the brain parenchyma, express the amyloid precursor protein (APP) that is otherwise prominent in pathological structures related to Alzheimer's disease. In this disease complex amyloid-bearing neuritic plaques contain beta A4-amyloid protein, the APP, and numerous inflammatory proteins. The accompanying activation of microglia has mostly been viewed as a secondary reaction to amyloid deposits. Activation of microglia was performed in a graded fashion. Transection of peripheral nerves such as the facial or sciatic nerve causes a microglial reaction within hours in the nucleus of origin or in projection areas of the CNS. A predominantly glial up-regulation of APP mRNA and protein could be detected as early as 6 h post lesion not only at the site of affected neuronal cell bodies but also in corresponding projection areas. Its time course suggests rapid transneuronal signalling to glial cells in the projection area. Light and electron microscopy demonstrate that microglia, which are cells of mononuclear phagocyte lineage and comprise up to 20% of all glial cells, are the dominant source for non-neuronal APP expression. Ultrastructurally, brain perivascular cells within the basal lamina constitutively express APP and thus are a possible source of vascular amyloid. Additionally, microglia express leukocyte-derived (L)-APP mRNA and protein that have recently been described in mononuclear cells of the immune system. Increased L-APP expression may serve as a potential marker for glial/microglial activation. Such immune-mediated amyloidogenesis initiated by microglia might have implications for the treatment of neurodegenerative diseases.
Amyloid beta-Protein Precursor↗
Planar polarity in the ciliated epidermis of Xenopus embryos.
The coordinated orientation of ciliary beat in the larval epidermis of amphibians, evident in an organized streamline pattern, suggests a planar polarity of the epithelium, i.e., a polarity within the plane of the cell sheet. It has been proposed that the direction of ciliary beat is determined at mid gastrula by a gradient of a diffusible factor produced by the mesoderm. To analyze whether ectoderm in isolation can establish a uniform direction of ciliary beat, and at what stage its polarity is specified in the embryo, ectoderm of Xenopus laevis embryos of different stages was cultured in vitro on substrates. On concanavalin A, ectoderm isolated at early gastrula stages, i.e., prior to any contact with mesoderm, can autonomously coordinate the direction of ciliary beat, at least in small regions. A uniform planar polarity is expressed by ectoderm explanted from the early mid gastrula onward. On fibronectin, which promotes migration, the direction of movement correlates well with the direction of ciliary beat, and directional migration can even override the inherent polarity specified prior to explantation. Embryos which lack dorsal mesoderm nevertheless develop a highly organized streamline pattern, excluding a strict requirement for dorsal mesoderm for the determination of planar polarity. However, in spite of the early specification of planar polarity found for isolated tissue, rotated ectodermal transplants in situ can readjust their polarity in accordance with that of the host.
Animals↗
Activation of blood neutrophils in acute episodes of farmer's lung.
Farmer's lung often presents clinically as recurring acute episodes several hours after exposure to moldy hay. During these episodes the blood neutrophil count increases. Because activated neutrophils release toxic oxygen metabolites and proteinases, we hypothesized that the pulmonary reaction in farmer's lung may be induced by the secretory products of activated neutrophils. To evaluate this concept, we quantified the respiratory burst of separated blood neutrophils from patients with farmer's lung (n = 12) during standardized exposure tests with moldy hay. The respiratory burst of these cells was evaluated by measuring zymosan-stimulated and lucigenin-amplified chemiluminescence (CL). Asymptomatic farmers (n = 12) and normal volunteers with no prior exposure to moldy hay (n = 15) were used as control subjects. As expected, following exposure in the group of patients with farmer's lung, striking changes in VC, TLCO, and PaO2 were observed, whereas there were only minor changes in these parameters in both control groups. In all three groups a considerable increase in the blood leukocyte count was observed. The CL response of the blood neutrophils from patients with farmer's lung 6 h after exposure was significantly higher than before or 1 h after exposure (p < 0.05 for both comparisons), whereas there was no significant change in the CL response in either control group during the observation period. Our results indicate that antigen inhalation induces an increase in the number of circulating neutrophils in patients and controls, but in patients with an acute episode of farmer's lung the neutrophils are primed for an enhanced respiratory burst and may thereby damage the lung.
Acridines↗